Polypeptide for repairing mucosal damage or skin wound and use thereof

ABSTRACT

Provided are a new polypeptide for repairing mucosal damage or a skin wound, and the use thereof. The polypeptide is not homologous with known polypeptides, can be stably present in vivo and in vitro, and has the effect of regulating stem cell proliferation and differentiation to repair mucosal damage or a skin wound. The present invention further relates to the use of the new polypeptide in the repairing of mucosal damage or a skin wound by means of regulating stem cell proliferation and differentiation, and the use thereof in the prevention, alleviation or treatment of gastrointestinal diseases.

TECHNICAL FIELD

Provided is a novel polypeptide for repairing mucosal damage or skinwounds and the use thereof. The polypeptide provided herein has nohomology with any known polypeptides, can exist stably both in vivo andin vitro, and has the effect of regulating the proliferation anddifferentiation of stem cells to repair mucosal damage or skin injury.In addition, Provided is the use of the novel polypeptide in repairingmucosal damage or skin wounds by regulating the proliferation anddifferentiation of stem cells and in preventing, alleviating or treatinga gastrointestinal disease.

BACKGROUND ART

Skin wounds and/or mucosal damage are common pathologicalcharacteristics of many diseases. Skin wounds or skin injury refers todamage to normal skin (tissue) caused by external injury-causing factorssuch as surgery, external forces, heat, electric current, chemicals andlow temperatures and internal factors in the body such as local bloodsupply disturbance. Skin injury is often accompanied by the destructionof skin integrity and loss of a certain amount of normal tissues; inaddition, the normal function of the skin is impaired. It is alsoreferred to as a wound or trauma. At present, proteins/polypeptidedrugs, including basic fibroblast growth factor, epidermal growthfactor, platelet growth factor, granulocyte-macrophagecolony-stimulating factor, growth hormone, etc., have obvious woundhealing, skin care, anti-wrinkle, and anti-aging effects. However, theseproteins/polypeptide drugs have relatively long amino acid sequences,leading to the disadvantages of high preparation cost and poorstability, so the application thereof is limited to some extent.

Human mucosa refers to the inner layers of the respiratory system,digestive system, genitourinary system and other cavities or cysticmuscular organs. It is the second largest barrier in the human bodyafter skin and includes the oral cavity, pharynx, trachea, esophagus,stomach, intestine, vagina, bladder, etc. The tube walls or bladderwalls of these organs all have the same stratification rules and alsohave characteristics that are compatible with the functions thereof. Theembryonic origins, tissue structures, pathological processes, clinicalmanifestations, prognosis etc. thereof all have common characteristics.

Chronic gastritis is a chronic inflammation of gastric mucosa, which isa common and frequently occurring disease in gastroenterology.Clinically, chronic inflammation of gastric mucosa caused by variouscauses (i.e., manifested as infiltration of monocytes and lymphocytes inpathology) and (or) glandular atrophic lesions are called chronicgastritis. Chronic atrophic gastritis (CAG), which is characterized byatrophy of gastric mucosa epithelium and glands, has a hidden onset,long course, non-specific symptoms, is difficult to cure, accounts for11-31% among chronic gastritis, and it is common in middle-aged andelderly people. The onset thereof is associated with age and has nothingto do with gender. The disease has a slow onset, a lingering tendency,slow recovery, and treatment difficulties. Chronic atrophic gastritis isan important stage in the occurrence and development of gastric cancerand is regarded as a gastric precancerous lesion. In 1978, the WorldHealth Organization (WHO) classified CAG as a precancerous state, whichis often accompanied by precancerous lesions such as pseudopyloricmetaplasia and intestinal metaplasia or atypical hyperplasia phase.Especially for those with diffuse intestinal metaplasia or atypicalhyperplasia, canceration is more likely to occur. Most professionals inthe field agree with the development mode of chronic superficialgastritis, atrophic gastritis, intestinal metaplasia, dysplasia andintestinal gastric cancer. Therefore, early accurate diagnosis andtreatment are of great significance to patients with chronic atrophicgastritis. At present, modern medicine mainly treats this disease bymeans of symptom improvement and surgical intervention, and there is yetno good strategy for gland atrophy and intestinal metaplasia. CAG is animportant stage for the transformation of chronic gastritis into gastriccancer. Active treatment of CAG is of far-reaching significance toprevent its canceration and reduce the incidence of gastric cancer.Seeking for an effective method for treating atrophic gastritis is oneof the important measures to better prevent gastric cancer.

Clinically, mucosal tissue injuries may lead to gastrointestinaldiseases such as chronic gastritis and digestive tract ulcers. There aretwo different mechanisms for mucosal epithelium repair, i.e.,restitution and regeneration or renewal (Cur. Med. Chem., 2008, 15,3133-3144). Restitution or recovery generally begins within a fewminutes after injury, and superficial lesions are quickly repaired bycell migration. Regeneration refers to continuous regeneration throughdifferentiation and proliferation of stem cells and progenitor cells,which lasts for several days to several months.

Epidermal growth factor (EGF) is a polypeptide composed of 53 amino acidresidues, which widely exists in various tissues, organs and body fluidsand can promote epithelial cell proliferation to protect the skin.Epidermal growth factor mainly promotes the proliferation and growth ofskin tissue cells, so that new cells can replace aging cells, thushaving anti-aging, skin care and health care functions, etc. Epidermalgrowth factor has been reported to have the function of repairingwounds. When skin wounds need to be disinfected and debrided,disinfectants containing iodine or hydrogen peroxide will be used, andas a result, EGF is unstable under this condition. Growth factors arerelated to healing from gastrointestinal anastomosis (J. Surgical Res.2014; 17:202-210); however, when EGF is orally administered through thegastrointestinal tract, it degrades after entering the body and cannotachieve therapeutic effects.

Therefore, there is a need for a peptide substance which is stable invivo and in vitro and can treat skin and/or mucosal damage, especiallygastrointestinal mucosal damage.

SUMMARY OF THE INVENTION

In order to overcome the deficiencies and defects in the prior art, anobject of the present invention is to provide a novel class ofpolypeptides.

In a first aspect, Provided is a compound of Formula (I) or aphysiologically compatible salt thereof, wherein the compound of Formula(I) is as follows:

H-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Val-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁-OH  (I)

wherein

-   -   Xaa₁ is Pro, Gly, Ala or absent;    -   Xaa₂ is Ala, Leu, Ile, Gly, Cys, Ser or absent;    -   Xaa₃ is Ala, Pro, Gly, Leu, Ile, Cys, Ser or absent;    -   Xaa₄ is Glu, Gln, Asp, Asn, Leu, Ile, Val or absent;    -   Xaa₅ is Pro, Gly, Ala, Val or absent;    -   Xaa₆ is Pro, Gly or Ala;    -   Xaa₇ is Leu, Phe, Val, Ala, Tyr, Glu, Lys, Asp, Ile, Met or        absent;    -   Xaa₈ is Val, Leu, Gln, Ile, Met or absent;    -   Xaa₉ is Lys, Arg, His, Asp, Val or absent;    -   Xaa₁₀ is Glu, Gln, Asp, Asn or absent; and    -   Xaa₁₁ is Glu, Asp, Asn, Gln or absent,

provided that at most 9 of Xaa₁, Xaa₂, Xaa₃, Xaa₄, Xaa₅, Xaa₇, Xaa₈,Xaa₉, Xaa₁₀ and Xaa₁₁ are absent.

In one embodiment, X_(aa5) is Pro.

In one embodiment, X_(aa6) is Pro.

In one embodiment, X_(aa7) is Leu.

In one embodiment, the compound of Formula (I) has a structure of thefollowing Formula (II):

H-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Pro-Val-Pro-Leu-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁-OH  (II),

wherein

-   -   Xaa₁ is Pro, Gly, Ala or absent;    -   Xaa₂ is Ala, Leu, Ile, Gly, Cys, Ser or absent;    -   Xaa₃ is Ala, Pro, Gly, Leu, Ile, Cys, Ser or absent;    -   Xaa₄ is Glu, Gln, Asp, Asn, Leu, Ile, Val or absent;    -   Xaa₈ is Val, Leu, Gln, Ile, Met or absent;    -   Xaa₉ is Lys, Arg, His, Asp, Val or absent;    -   Xaa₁₀ is Glu, Gln, Asp, Asn or absent; and    -   Xaa₁₁ is Glu, Asp, Asn, Gln or absent.

In one embodiment, Xaa₁ in Formula (I) or (II) is Pro or absent;preferably Pro.

In one embodiment, Xaa₂ in Formula (I) or (II) is Ala or absent;preferably Ala.

In one embodiment, Xaa₃ in Formula (I) or (II) is Ala, Gly or absent;preferably Ala.

In one embodiment, Xaa₄ in Formula (I) or (II) is Glu, Gln, Asp orabsent; preferably Glu, Asp or Gln.

In one embodiment, Xaa₈ in Formula (I) or (II) is Val or absent;preferably Val.

In one embodiment, Xaa₉ in Formula (I) or (II) is Lys, Arg or absent;preferably Lys or absent.

In one embodiment, Xaa₁₀ in Formula (I) or (II) is Glu, Gln or absent;preferably Gln.

In one embodiment, Xaa₁₁ in Formula (I) or (II) is Asp or absent;preferably Asp.

In one embodiment, one of Xaa₁, Xaa₂, Xaa₃ and Xaa₄ in Formula (I) or(II) is absent; or two of Xaa₁, Xaa₂, Xaa₃ and Xaa₄ in Formula (I) or(II) are absent; or three of Xaa₁, Xaa₂, Xaa₃ and Xaa₄ in Formula (I) or(II) are absent; or all of Xaa₁, Xaa₂, Xaa₃ and Xaa₄ in Formula (I) or(II) are absent.

In one embodiment, one of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ in Formula (I) or(II) is absent; or two of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ in Formula (I) or(II) are absent; or three of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ in Formula (I)or (II) are absent; or all of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ in Formula (I)or (II) are absent.

In one embodiment, the compound is selected from any one of Compounds1-73 of the present invention.

In one embodiment, the compound is selected from:

-   -   Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 1);    -   Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys (Compound 3);    -   Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 10);    -   Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu (Compound 26);    -   Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 27);    -   Ala-Glu-Pro-Val-Pro-Leu (Compound 30);    -   Glu-Pro-Val-Pro-Leu (Compound 31);    -   Pro-Val-Pro-Leu (Compound 32);    -   Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 28);    -   Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 11);    -   Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 48);    -   Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp (Compound 57);        or    -   Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 38).

For convenience, when the compound of the present invention is describedin the present application, H on the left side and OH on the right sideare omitted.

In one embodiment, the compound isPro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 1).

In a second aspect, Provided is a method for repairing mucosal damage,the method comprising administering the compound of the presentinvention or a physiologically compatible salt thereof to a subject orbringing the mucosal damage into contact with the compound of thepresent invention or the physiologically compatible salt thereof. In oneembodiment, the repair is carried out by regulating the proliferationand differentiation of stem cells.

In one embodiment, the mucosal damage is mucosal damage in a cavity suchas the digestive system or respiratory system.

The mucosal damage of the digestive system is related to oral,esophageal and gastrointestinal diseases, and oral diseases include oralulcer, stomatitis, gingivitis, periodontitis, etc.; the esophagealdiseases include esophagitis, esophageal ulcer, etc.; and thegastrointestinal diseases include, without limitation, chronicgastritis, chronic atrophic gastritis, acute gastritis, gastroduodenalulcer, functional gastrointestinal diseases, dyspepsia, precancerouslesions, digestive system tumors, gastrointestinal bleeding,gastroesophageal reflux disease, acute and chronic enteritis, ulcerativecolitis, Crohn's disease, and mucosal injuries caused by radiotherapyand/or chemotherapy.

In a preferred embodiment, the digestive tract mucosa includes gastricmucosa and intestinal mucosa. In a preferred embodiment, chronicgastritis includes chronic atrophic gastritis. In a preferredembodiment, the mucosal damage is gastric mucosal damage caused by anirritant substance or a drug or by a stress state. The irritantsubstance is, for example, hydrochloric acid, ethanol or alcohol, etc.,and the drug is, for example, the non-steroidal anti-inflammatory drugaspirin or indomethacin, etc.

Provided is a method for preventing, alleviating or treating a digestivetract disease or eliminating inflammatory edema, the method comprisingadministering the compound of the present invention or a physiologicallycompatible salt thereof to a subject. The digestive tract diseaseincludes those associated with oral, esophageal and gastrointestinaldiseases, and the oral diseases include oral ulcer, stomatitis,gingivitis, periodontitis, etc.; the esophageal diseases includeesophagitis, esophageal ulcer, etc.; and the gastrointestinal diseasesinclude, without limitation, chronic gastritis, chronic atrophicgastritis, acute gastritis, gastroduodenal ulcer, functionalgastrointestinal diseases, dyspepsia, precancerous lesions, digestivesystem tumors, gastrointestinal bleeding, gastroesophageal refluxdisease, acute and chronic enteritis, ulcerative colitis, Crohn'sdisease, and mucosal injuries caused by radiotherapy and/orchemotherapy. In one embodiment, the prevention, alleviation ortreatment of digestive tract disease is carried out by regulating theproliferation and differentiation of stem cells. The method can prevent,alleviate or treat a gastrointestinal disease by means of the protectiveeffect of the compound of the present invention or a physiologicallycompatible salt thereof on digestive tract mucosae such as gastricmucosa or intestinal mucosa or by repairing the injury of digestivetract mucosae such as gastric mucosa or intestinal mucosa.

Provided is a method for repairing a mucosal or skin wound, the methodcomprising administering the compound of the present invention or aphysiologically compatible salt thereof to a subject. In one embodiment,the repair of the mucosal or skin wounds surface includes the regulationof the proliferation and differentiation of stem cells.

In the above method of the present invention, the compound of thepresent invention or a physiologically compatible salt thereof isadministered orally, by injection, subcutaneously, etc.

In a third aspect, Provided is a method for repairing skin wound, themethod comprising bringing the skin wounds into contact with thecompound of the present invention or a physiologically compatible saltthereof. In a preferred embodiment, the skin wounds is related to, butnot limited to, epidermal inflammation, mechanical and surgical wound,burns and scalds, ulcers, fistulas, bedsores, and skin injuries causedby radiotherapy and/or chemotherapy. In one embodiment, the skin woundsrefers to damage to normal skin caused by external injury-causingfactors such as surgery, external forces, heat, electric current,chemicals and low temperatures and internal factors in the body such aslocal blood supply disturbance. In one embodiment, the skin wounds isoften accompanied by the destruction of skin integrity and loss of acertain amount of normal tissues. In another embodiment, the skin woundsinclude the impairment of the normal function of the skin. In oneembodiment, the recovery of the skin wounds is carried out by regulatingthe proliferation and differentiation of stem cells.

Provided is a method for promoting the proliferation of HaCAT cells, themethod comprising bringing the cells into contact with the compound ofthe present invention or a physiologically compatible salt thereof.

In a fourth aspect, Provided is a method for regenerating an injuredblood vessel, the method comprising bringing the injured blood vesselinto contact with the compound of the present invention or aphysiologically compatible salt thereof. In a preferred embodiment, theinjured blood vessel includes blood vessel injuries caused by digestivetract mucosa injury and skin wounds.

In a fifth aspect, Provided is a pharmaceutical composition, a foodcomposition, a health care or cosmetic composition, or commoditycomposition, said composition comprising the compound of the presentinvention or a physiologically compatible salt thereof and aphysiologically acceptable carrier. In one embodiment, thephysiologically acceptable carrier includes a pharmaceuticallyacceptable carrier or a cosmetically acceptable carrier. The compositionfor a medicament, a food product, a health care product or a cosmeticproduct, or a daily product can be prepared according to a conventionaltechnique of pharmaceutics or cosmetics, including mixing the compoundof the present invention, which acts as an active ingredient, with acarrier, and preparing the mixture into the desired dosage formaccording to a conventional technique. According to requirements, thecomposition of the present invention can be formulated into an oralpreparation, a mucosal preparation, an injection preparation, aninhalation preparation and a topical preparation.

The polypeptide Provided has no homology with known polypeptides, whichfacilitates artificial polypeptide synthesis to obtain a high-puritypolypeptide. Compared with epidermal growth factor polypeptides, thepolypeptide Provided is stable in vivo because it only consists of atmost 12 amino acid residues. Moreover, the polypeptide Provided canpromote the proliferation and differentiation of stem cells,particularly the proliferation and differentiation of gastric organoids,participate in and regulate the proliferation and differentiation ofgastric epithelial stem cells, so as to repair the injury ofgastrointestinal stem cells and epidermal stem cells, and has theeffects of significantly alleviating the pathological development ofgastrointestinal diseases such as chronic gastritis and digestive tractulcers, eliminating inflammatory edema, promoting the repair ofdigestive tract mucosa injury and skin wound, shortening the woundhealing time, modulating immune functions, etc. In addition, thepolypeptide Provided, when applied to a skin wounds surface of the bodysurface, can function even after the skin wounds surface is sterilizedby an iodine preparation or hydrogen peroxide, or can stably exist evenin an artificial gastric juice, an artificial intestinal juice, etc.,whereas the epidermal growth factor, when applied to the skin of thebody surface, will be structurally destroyed and cannot function afterdisinfection with an iodine preparation or hydrogen peroxide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic diagram of the steps of the solid-phasesynthesis of a polypeptide.

FIG. 2 shows the anti-ulcer effect of Compound 1 on ethanol-inducedgastric ulcer in mice.

FIG. 3 shows the results of Compound 1 on promoting the proliferationand differentiation of gastric organoids.

FIG. 4 shows the results of Compound 1 promoting the differentiation ofgastric organoids.

FIG. 5 shows the therapeutic effect of Compound 1 on mice with chronicatrophic gastritis.

FIG. 6 shows the effect of Compound 1 on gastric epithelial stem cellsin rats with chronic atrophic gastritis.

FIG. 7 shows the therapeutic effect of Compound 1 on rats with chronicatrophic gastritis.

FIG. 8 shows the proliferation-promoting effect of Compound 1 on HaCATcells.

FIG. 9 shows a schematic diagram of the analysis site of thesubintestinal vascular area of zebrafish.

FIG. 10 shows a typical diagram of the area of the subintestinalvascular area of zebrafish treated with the compound of the presentinvention.

FIG. 11 shows the number of subintestinal vascular branches of zebrafishtreated with the compound of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

The term “physiologically compatible salt” refers to a salt form that isphysiologically compatible (i.e., pharmacologically acceptable) andsubstantially non-toxic to an individual to whom the compound of thepresent invention is to be administered. Physiologically compatiblesalts of the compound of the present invention include conventional andstoichiometric acid addition salts or base addition salts formed fromsuitable, non-toxic organic or inorganic acids or inorganic bases.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human. Specifically, the term “subject” relates to a mammalor human with skin wounds and/or mucosal damage. It should be understoodby those skilled in the art that the repair of skin wounds and/ormucosal damage in the present invention can be applied for cosmeticpurposes (i.e., non-therapeutic purposes) and therapeutic purposes. Tothis end, the term “skin injury” in the present application furtherincludes skin injuries to be repaired for cosmetic purposes, such aswrinkles (e.g., wrinkles caused by ultraviolet radiation), skin lines,cracks, lumps, large pores (e.g., those related to accessory structuressuch as sweat ducts, sebaceous glands or hair follicles), or unevennessor roughness, loss of skin elasticity (loss and/or inactivation offunctional skin elastin), sagging (including dropsy of eyes and jaw),loss of skin hardness, loss of skin firmness, loss of recovery abilityafter skin deformation, discoloration (including dark circles undereyes), macula and blisters, sallow complexion, hyperpigmented skin areassuch as senile plaques and freckles, cutin, abnormal differentiation,excessive keratinization, degenerated elastic tissues, destructedcollagen, and other tissue changes in skin keratin, dermis, epidermis,skin vascular systems (such as telangiectasia or multi-branched bloodvessels) and subcutaneous tissues, especially those close to the skin.

The following is a description of the present invention in conjunctionwith specific trials and is not a limitation on the scope of protectionof the present invention.

TABLE 1 English names or abbreviations of reagents and solvents used inwriting English name or abbreviation Chinese name HBTUBenzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate MethanolMethanol Tert-Butyl methyl ether Tert-Butyl methyl ether Ethanol EthanolAA Amino acid

Example 1: Chemical Synthesis of Polypeptide

A polypeptide compound was synthesized by a conventional solid-phasesynthesis method via multiple cyclic processes of resin swelling,substitution, deprotection, washing, amino acid dissolution, amino acidactivation and condensation processes, washing, and furtherdeprotection, and finally cleavage and side chain deprotection.

The schematic diagram of the steps of the solid-phase synthesis of thepolypeptide was shown in FIG. 1 . In FIG. 1 , Cl-2-Cl-Resin represented2-chlorotrityl chloride resin; Fmoc-Aa(n) represented an amino acid with9-fluorenylmethoxycarbonyl; DIPEA was N,N-diisopropylethylamine; DCM wasdichloromethane; PIP was piperidine; DMF was N,N-dimethylformamide; HOBtwas 1-hydroxybenzotriazole; DIC was N,N′-diisopropyl carbodiimide; TFAwas trifluoroacetic acid; and TIPS was triisopropylsilane.

Hereinafter, taking Compound 1(Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp) as an example, amethod for the synthesis and purification of Compound 1 was shown, themethod comprising step 1. preparation of fully protected peptide resin;2. cutting and deprotection; and 3. purification (salt exchange) andfreeze-drying.

1. Preparation of Fully Protected Peptide Resin

(1) Resin swelling: 2.0192 g of 2-Chlorotrityl Chloride Resin (S=0.73mmol/g) was weighed, added to a synthesis tube with a sieve plate,swelled with 40 ml of dichloromethane for 30 min, and subjected tosuction filtration to remove dichloromethane.

(2) Preparation of Fmoc-Asp(OtBu)-Resin: Based on a molar ratio of1:1.5:1.65 of resin to Fmoc-Asp(OtBu)-OH to DIPEA, Fmoc-Asp(OtBu)-OH andDIPEA were respectively weighed, dissolved in 20 ml of dichloromethaneand added to the synthesis tube. Bubbling with N₂ and shaking wereperformed at room temperature for 1-3 hours, and 2 ml of methanol wasdirectly added to the reaction solution, followed by blocking for 30min. It was then washed 4 times separately with dimethylformamide, 25 mleach time, and the resin was dried by draining.

(3) Removal of Fmoc protecting group: 20 ml of a 20% piperidine-DMF(v/v) solution was added to the reactor, the reaction was bubbled withN₂ for 20 min, and draining was performed; and it was then washed withdimethylformamide 6 times, 25 ml each time, 3 min each time, and afterdraining, the results of Fmoc removal were detected by ninhydrin method.

(4) Amino acid pre-activation: 4.38 mmol of Fmoc-protected amino acid,5.26 mmol of HOBt, 4.60 mmol of DIC were added to a 250 ml round bottomflask, dissolved in 20 ml of 1:1 DCM-DMF (v/v), and pre-activated in anice bath at −5° C. to 0° C. under stirring for 30-60 min.

(5) Amino acid connection: the activated protected amino acid solutionwas poured into the reactor, and an appropriate amount of DCM wassupplemented to clean the tools. After the reaction was bubbled with N₂at room temperature for 1-3 hours, ninhydrin method was used to detectwhether the amino acid connection was complete and if so, draining wasperformed. The resin was washed with dimethylformamide 4 times, 25 mleach time, 3 min each time, and draining was performed. The amount ofeach amino acid and condensing agent and the specific reaction time wereshown in Table 2.

(6) After the condensation of the first amino acid was complete, steps(3) to (5) were repeated to extend the peptide chain according to theamino acid sequence until the coupling of the last amino acid wascompleted.

(7) The resin peptide was washed with dichloromethane 6 times, 25 mleach time, 3 min each time, and draining was performed.

TABLE 2 Amounts of amino acids and condensing agent Amino acid Aminoacid name AA/eq amount/g HOBt/g DIPEA/g DIC/g Fmoc-L-Asp(OtBu)—OH 2.190.90 0 0.31 0 Fmoc-L-Gln(Trt)-OH 4.38 2.67 0.71 0.57 0.58Fmoc-L-Lys(Boc)-OH 4.38 2.05 0.71 0.57 0.58 Fmoc-L-Val-OH 4.38 1.49 0.710.57 0.58 Fmoc-L-Leu-OH 4.38 1.55 0.71 0.57 0.58 Fmoc-L-Pro-OH 4.38 1.480.71 0.57 1.16 Fmoc-L-Val-OH 4.38 1.49 0.71 0.57 0.58 Fmoc-L-Pro-OH 4.381.48 0.71 0.57 1.16 Fmoc-L-Glu(OtBu)—OH•H₂O 4.38 1.94 0.71 0.57 1.16Fmoc-L-Ala-OH•H₂O 4.38 1.44 0.71 0.57 1.16 Fmoc-L-Ala-OH•H₂O 4.38 1.440.71 0.57 1.16 Fmoc-L-Pro-OH 4.38 1.48 0.71 0.57 1.16

Step 2. Cleavage and Deprotection

(1) 50 ml of a cleaving agent (TFA:TIPS:H₂O=95:2.5:2.5, v/v) was addedto the synthesis tube in step 1, and the reaction was bubbled with N₂for 1.5-3 hours.

(2) After the cleavage reaction was complete, the cleavage agent wassuction-filtered into a 250 ml round bottom flask. After vacuumconcentration to one third of the original volume of the cleavage agent,add 10 folds of the existing volume of methyl tert-butyl ether wasadded, and the mixture was stirred for 30 min. The resulting mixedsolvent was filtered and washed three times separately with 30 ml ofmethyl tert-butyl ether, and the resulting crude peptide product was putinto a sand core funnel and dried with N₂ in a fume hood, so that thesolvent was volatilized until the crude peptide became powder. Theobtained crude peptide was 1.87 g and had a crude yield of 85.1%.

Step 3. Purification (Salt Exchange) and Freeze-Drying

Using the following chromatographic parameter condition A, the crudepeptide obtained in step 2 was purified by HPLC. Specifically, the crudepeptide obtained in step 2 was dissolved with water and/or acetonitrile,and filtered by a 0.45 μm filter membrane; sample injection wasperformed; gradient elution was performed with an acetonitrile-watermobile phase; a peptide eluent of interest was collected; and finally,rotary evaporation concentration was performed.

Chromatographic Parameter Condition A:

-   -   Chromatographic column: YMC-Actus Triart C18 30*250 mm;    -   Eluent A: 0.1% (v/v) TFA/H₂O;    -   Eluent B: acetonitrile;    -   Flow rate: 25 ml/min;    -   Ultraviolet detection wavelength: 220 nm;

TABLE 3 Gradient elution conditions Time, min Eluent A (%) Eluent B (%)0 90 10 30 75 25

Next, the product obtained in the previous step was subjected to saltexchange by HPLC method using the following chromatographic parametercondition B, whereby the final peptide Compound 1 was obtained.Specifically, 95% Al+5% B balanced chromatographic column was used;sample injection was then performed; next, 95% A2+5% B balancedchromatographic column was used; gradient elution was performed with Aland B; a peptide eluent of interest was collected; and finally, rotaryevaporation concentration and freeze-drying were performed to obtainCompound 1 (purification yield 73.3%, purity 100%). The structure ofCompound 1 was confirmed by MS and ¹H-NMR.

Chromatographic Parameter Condition B:

-   -   Chromatographic column: YMC-Actus Triart C18 30*250 mm    -   Eluent A1: 0.1 M acetic acid    -   Eluent A2: 0.025 M acetic acid+0.1 M ammonium acetate    -   Eluent B: acetonitrile    -   Flow rate: 25 ml/min    -   Ultraviolet detection wavelength: 220 nm

TABLE 4 Gradient elution conditions Time, min Eluent A1 (%) Eluent B (%)0 95 5 5 95 5 35 70 30

Other compounds were synthesized in a similar way to the synthesis ofCompound 1. The results were shown in Table 5 and the other parts of thedescription.

TABLE 5 Synthesized compounds Amount Yield of crude (after productpurifi- No. Compound sequence (g) cation) Purity MS  1Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.87 73.3% 100% 1263.70, 632.50Leu-Val-Lys-Gln-Asp (double charge), and 422.10 (triple charge)  2Gly-Ala-Ala-Glu-Pro-Val-Pro- 2.07 N/A 100.0% 612.60 (doubleLeu-Val-Lys-Gln-Asp charge)  3 Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.62 33.8% 99.8% 511.00 (double Leu-Val-Lys charge)  4Pro-Ala-Ala-Glu-Gly-Val-Pro- 2.00 56.8%  97.9% 612.60 (doubleLeu-Val-Lys-Gln-Asp charge)  5 Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.50 42.3% 99.2% 612.50 (double Leu-Val-Lys-Gln-Asp charge)  6Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.78 38.1% 100.0% 591.50 (doubleAla-Val-Lys-Gln-Asp charge)  7 Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.50 46.5%100.0% 605.50 (double Val-Val-Lys-Gln-Asp charge)  8Pro-Ala-Ala-Glu-Gly-Val-Gly- 2.15 14.4% 100.0% 592.50 (doubleLeu-Val-Lys-Gln-Asp charge)  9 Pro-Ala-Ala-Glu-Gly-Val-Gly- 2.12 67.9% 98.9% 713.40 Leu 10 Pro-Ala-Ala-Gln-Pro-Val-Pro- 2.36 57.4% 100.0%632.00 (double Leu-Val-Lys-Gln-Asp charge) 11Pro-Ala-Ala-Asp-Pro-Val-Pro- 2.39 52.9%  99.6% 625.50 (doubleLeu-Val-Lys-Gln-Asp charge) 12 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.95 78.3%100.0% 649.5 (double Phe-Val-Lys-Gln-Asp charge) and 433.4(triple charge) 13 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.66 38.4% 100.0%657.4 (double Tyr-Val-Lys-Gln-Asp charge) and 438.8 (triple charge) 14Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.92 53.5% 100.0% 490.9 (double Leu-Val-Lyscharge) 15 Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.81 56.9% 100.0% 483.8 (doubleVal-Val-Lys charge) 16 Pro-Ala-Ala-Glu-Pro-Val-Ala- 1.98 60.1% 100.0%497.8 (double Leu-Val-Lys charge) 17 Pro-Ala-Ala-Glu-Pro-Val-Ala- 2.0457.3% 100.0% 490.9 (double Val-Val-Lys charge) 18Pro-Ala-Ala-Glu-Ala-Val-Pro- 2.15 52.0% 100.0% 619.5 (doubleLeu-Val-Lys-Gln-Asp charge) 19 Pro-Ala-Ala-Glu-Pro-Val-Ala- 1.92 37.7%100.0% 619.4 (double Leu-Val-Lys-Gln-Asp charge) 20Pro-Ala-Ala-Glu-Ala-Val-Ala- 1.96 19.1%  99.7% 606.50 (doubleLeu-Val-Lys-Gln-Asp charge) 21 Ala-Ala-Ala-Glu-Pro-Val-Pro- 2.58 61.6%100.0% 619.50 (double Leu-Val-Lys-Gln-Asp charge) 22Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.11 53.8% 100.0% 527.8 (double Phe-Val-Lyscharge) 23 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.05 51.1% 100.0% 535.8 (doubleTyr-Val-Lys charge) 24 Pro-Ala-Ala-Glu-Pro-Val-Gly- 1.81 55.5% 100.0%507.9 (double Phe-Val-Lys charge) 25 Pro-Ala-Ala-Glu-Pro-Val-Ala- 1.8159.0% 100.0% 514.8 (double Phe-Val-Lys charge) 26Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.57 60.3% 100.0% 793.4 and 397.3 Leu(double charge) 27 Ala-Glu-Pro-Val-Pro-Leu-Val- 2.52 48.3% 100.0%548.5 (double Lys-Gln-Asp charge) 28 Pro-Val-Pro-Leu-Val-Lys-Gln- 2.0543.6% 100.0% 448.40 (double Asp charge) 29 Pro-Ala-Ala-Glu-Pro-Val-Pro1.62 55.4% 100.0% 680.40 30 Ala-Glu-Pro-Val-Pro-Leu 2.70 71.7% 100.0%625.10 31 Glu-Pro-Val-Pro-Leu 1.82 52.2%  97.9% 554.40 32Pro-Val-Pro-Leu N/A 46.4% 100.0% 425.30 33 Ala-Ala-Glu-Pro-Val-Pro-Leu3.02 60.3% 100.0% 696.40 34 Pro-Ala-Ala-Glu-Pro-Val 2.50 94.3% 100.0%583.40 35 Pro-Ala-Ala-Glu-Pro 2.05 59.3%  99.2% 484.30 36Pro-Ala-Ala-Glu 2.53 65.3% 100.0% 387.30 37 Ala-Ala-Glu-Pro-Val-Pro-Leu-2.54 N/A 100.0% 584.10 (double Val-Lys-Gln-Asp charge) 38Glu-Pro-Val-Pro-Leu-Val-Lys- 2.48 56.0%  94.1% 513.00 (double Gln-Aspcharge) 39 Val-Pro-Leu-Val-Lys-Gln-Asp 1.95 57.9% 100.0% 399.90 (doublecharge) 40 Pro-Leu-Val-Lys-Gln-Asp 1.82 49.8% 100.0% 350.30 (doublecharge) 41 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.04 58.5%  99.6% 511.00 (doubleIle-Val-Lys charge) 42 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.22 56.7%  98.7%504.00 (double Val-Val-Lys charge) 43 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.2248.8%  98.6% 520.10 (double Met-Val-Lys charge) 44 Ala-Glu-Pro-Val-Pro2.37 47.8% 100.0% 512.40 45 Ala-Glu-Pro-Val 0.43 57.8% 100.0% 415.30 46Pro-Ala-Ala-Asn-Pro-Val-Pro- 2.58 57.5% 100.0% 625.10 (doubleLeu-Val-Lys-Gln-Asp charge) 47 Pro-Ala-Ala-Leu-Pro-Val-Pro- 2.68 57.9%100.0% 624.50 (double Leu-Val-Lys-Gln-Asp charge) 48Pro-Ala-Gly-Glu-Pro-Val-Pro- 2.74 56.7% 100.0% 625.50 (doubleLeu-Val-Lys-Gln-Asp charge) 49 Pro-Ala-Pro-Glu-Pro-Val-Pro- 2.92 22.2%100.0% 645.40 (double Leu-Val-Lys-Gln-Asp charge) 50Pro-Ala-Ala-Glu-Pro-Val-Pro- 3.10 48.4% 100.0% 632.10 (doubleLeu-Val-Lys-Gln-Asn charge) 51 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.71 53.9%100.0% 618.00 (double Leu-Val-Val-Gln-Asp charge) 52Pro-Ala-Ala-Glu-Pro-Val-Pro- 3.13 57.1% 100.0% 625.60 (doubleVal-Val-Lys-Gln-Asp charge) 53 Pro-Ala -Ala-Glu-Pro-Val-Pro- 3.25 53.5%100.0% 632.60 (double Ile-Val-Lys-Gln-Asp charge) 54Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.82 59.4% 100.0% 641.60 (doubleMet-Val-Lys-Gln-Asp charge) 55 Pro-Leu-Ala-Glu-Pro-Val-Pro- 2.34 62.7%100.0% 653.60 (double Leu-Val-Lys-Gln-Asp charge) 56Pro-Ile-Ala-Glu-Pro-Val-Pro- 3.22 41.9% 100.0% 653.60 (doubleLeu-Val-Lys-Gln-Asp charge) 57 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.38 61.3%100.0% 633.10 (double Leu-Val-Lys-Glu-Asp charge) 58Pro-Ala-Ala-Glu-Pro-Val-Pro- 3.10 57.7% 100.0% 625.60 (doubleLeu-Val-Lys-Asn-Asp charge) 59 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.66 51.7% 99.5% 626.10 (double Leu-Val-Lys-Asp-Asp charge) 60Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.91 80.8%  99.5% 639.60 (doubleLeu-Val-Lys-Gln-Glu charge) 61 Pro-Ala-Leu-Glu-Pro-Val-Pro- 2.14 64.7%100.0% 653.60 (double Leu-Val-Lys-Gln-Asp charge) 62Pro-Ala-Ile-Glu-Pro-Val-Pro- 1.93 72.1% 100.0% 653.60 (doubleLeu-Val-Lys-Gln-Asp charge) 63 Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.21 61.8%100.0% 639.60 (double Leu-Leu-Lys-Gln-Asp charge) 64Pro-Ala-Ala-Glu-Pro-Val-Pro- 2.53 57.2% 100.0% 639.60 (doubleLeu-Ile-Lys-Gln-Asp charge) 65 Pro-Ala-Ala-Glu-Pro-Val-Pro- 3.17 33.3%100.0% 648.50 (double Leu-Met-Lys-Gln-Asp charge) 66Pro-Ala-Ala-Glu-Pro-Val-Pro- 1.35 49.8% 100.0% 646.60 (doubleLeu-Val-Arg-Gln-Asp charge) 67 Pro-Ala-Ala-Val-Pro-Val-Pro- 2.24 54.4%100.0% 617.60 (double Leu-Val-Lys-Gln-Asp charge) 68Val-Pro-Leu-Val-Lys-Gln-Asp 1.68 53.3% 100.0% 399.90 (double charge) 69Gly-Ala-Ala-Val-Pro-Val-Pro- 1.66 58.9% 100.0% 597.60 (doubleLeu-Val-Lys-Gln-Asp charge) 70 Gly-Ala-Gly-Val-Pro-Val-Pro- 2.42 45.0%100.0% 590.60 (double Leu-Val-Lys-Gln-Asp charge) 71Gly-Ala-Gly-Val-Gly-Val-Pro- 1.94 54.5% 100.0% 570.50 (doubleLeu-Val-Lys-Gln-Asp charge) 72 Pro-Ala-Ala-Glu-Pro-Val-Ala- 3.20 43.3%100.0% 636.60 (double Phe-Val-Lys-Gln-Asp charge) 73 Val-Pro-Leu-Val2.37 58.3% 100.0% 427.40 Note: Double charge represented 1/2 target peakin the mass spectrum, and triple charge represented 1/3 target peak inthe mass spectrum; N/A represented having difficulties in weighing, andno actual weight was considered.

Compound 1: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.27 (d, J=7.6 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H),8.09 (d, J=7.5 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H),7.94 (dd, J=16.7, 8.0 Hz, 2H), 7.58 (d, J=6.3 Hz, 1H), 7.51 (d, J=8.6Hz, 1H), 7.16 (s, 1H), 6.70 (s, 1H), 4.48 (dd, J=13.3, 7.9 Hz, 1H), 4.39(dd, J=8.2, 4.2 Hz, 1H), 4.35-4.21 (m, 6H), 4.18-4.03 (m, 3H), 3.71-3.47(m, 5H), 2.93-2.69 (m, 4H), 2.45-2.32 (m, 2H), 2.25 (t, J=7.7 Hz, 2H),2.08 (t, J=7.9 Hz, 2H), 2.01-1.93 (m, 3H), 1.93-1.84 (m, 14H, AcOH),1.84-1.76 (m, 3H), 1.75-1.57 (m, 8H), 1.54-1.39 (m, 5H), 1.36-1.27 (m,2H), 1.21-1.10 (m, 6H), 0.91-0.74 (m, 18H).

Compound 3: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys Acetate

¹H NMR (600 MHz, DMSO) δ 8.22-8.13 (m, 2H), 8.10 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 4.52-4.43(m, 1H), 4.39-4.19 (m, 6H), 4.12-4.04 (m, 1H), 3.89 (d, J=5.9 Hz, 1H),3.67-3.46 (m, 6H), 2.85 (dt, J=10.2, 6.8 Hz, 1H), 2.80-2.73 (m, 1H),2.69 (s, 2H), 2.21 (t, J=7.4 Hz, 2H), 2.03-1.76 (m, 14H, AcOH), 1.73 (d,J=5.5 Hz, 1H), 1.70-1.61 (m, 4H), 1.61-1.52 (m, 3H), 1.47 (s, 4H), 1.26(s, 2H), 1.20-1.12 (m, 6H), 0.91-0.83 (m, 9H), 0.83-0.77 (m, 9H).

Compound 4: Pro-Ala-Ala-Glu-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, D₂O) δ 4.45-4.16 (m, 10H), 4.04 (d, J=8.1 Hz, 1H),3.93-3.76 (m, 3H), 3.67-3.58 (m, 1H), 3.42-3.28 (m, 2H), 2.94 (t, J=7.4Hz, 2H), 2.72 (qd, J=16.4, 6.0 Hz, 2H), 2.45-2.27 (m, 5H), 2.27-2.16 (m,1H), 2.11-1.86 (m, 17H, AcOH), 1.84-1.47 (m, 8H), 1.45-1.25 (m, 8H),0.91 (d, J=6.8 Hz, 3H), 0.89-0.73 (m, 15H).

Compound 5: Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, D₂O+D₃COD) δ 4.66-4.62 (m, 2H), 4.40 (dd, J=8.1, 5.9Hz, 1H), 4.35-4.21 (m, 6H), 4.03-3.98 (m, 2H), 3.92-3.81 (m, 2H),3.78-3.71 (m, 1H), 3.62 (dt, J=10.3, 7.1 Hz, 1H), 3.39-3.30 (m, 2H),2.96-2.87 (m, 4H), 2.51-2.35 (m, 3H), 2.32 (t, J=7.6 Hz, 2H), 2.26-2.19(m, 1H), 2.10-1.91 (m, 14H, AcOH), 1.91-1.78 (m, 2H), 1.78-1.71 (m, 1H),1.70-1.58 (m, 3H), 1.53 (d, J=3.6 Hz, 3H), 1.42-1.34 (m, 2H), 1.33 (d,J=7.2 Hz, 3H), 1.30 (d, J=7.2 Hz, 3H), 0.94-0.88 (m, 6H), 0.88-0.83 (m,9H), 0.82-0.79 (m, 3H).

Compound 8: Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.30-8.24 (m, 3H), 8.15 (d, J=7.3 Hz, 1H),8.11-8.03 (m, 2H), 7.94 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.80(t, J=9.4 Hz, 2H), 7.59 (d, J=6.4 Hz, 1H), 7.17 (s, 1H), 6.70 (s, 1H),4.44-3.99 (m, 10H), 3.82-3.57 (m, 7H), 2.94-2.69 (m, 5H), 2.47-2.41 (m,1H), 2.41-2.32 (m, 1H), 2.21 (t, J=7.9 Hz, 2H), 2.08 (t, J=7.9 Hz, 2H),2.03-1.79 (m, 11H, AcOH), 1.78-1.26 (m, 14H), 1.19 (dd, J=6.9, 4.7 Hz,6H), 0.87-0.76 (m, 18H).

Compound 9: Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu

¹H NMR (600 MHz, DMSO) δ 8.43 (d, J=7.6 Hz, 1H), 8.29-8.23 (m, 2H),8.22-8.14 (m, 2H), 7.81 (d, J=8.5 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H),4.32-4.08 (m, 5H), 3.78-3.69 (m, 4H), 3.63 (dd, J=16.4, 5.6 Hz, 1H),2.98-2.86 (m, 2H), 2.22 (t, J=7.9 Hz, 2H), 2.07-1.92 (m, 2H), 1.92-1.86(m, 1H), 1.79-1.64 (m, 4H), 1.62-1.54 (m, 1H), 1.50-1.40 (m, 2H), 1.19(dd, J=7.0, 1.3 Hz, 6H), 0.86-0.78 (m, 12H).

Compound 10: Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.28 (d, J=7.7 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H),8.07 (d, J=7.4 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 8.00 (d, J=7.3 Hz, 1H),7.95 (t, 2H), 7.58 (d, J=6.3 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.17 (d,J=15.3 Hz, 2H), 6.76 (s, 1H), 6.70 (s, 1H), 4.45 (q, J=13.6, 7.9 Hz,1H), 4.39 (dd, J=8.3, 4.1 Hz, 1H), 4.33-4.20 (m, 6H), 4.20-4.09 (m, 2H),4.09-4.02 (m, 1H), 3.69-3.47 (m, 5H), 2.86 (dt, J=10.2, 6.7 Hz, 1H),2.80-2.62 (m, 3H), 2.46-2.40 (m, 1H), 2.37 (dd, J=15.5, 2.7 Hz, 1H),2.14-2.03 (m, 4H), 2.02-1.76 (m, 16H, AcOH), 1.75-1.39 (m, 13H),1.39-1.22 (m, 2H), 1.22-1.11 (m, 6H), 1.00-0.68 (m, 18H).

Compound 11: Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.26 (d, J=7.6 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H),8.09 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.96 (t, J=7.4 Hz, 2H),7.87 (d, J=7.0 Hz, 1H), 7.60 (d, J=6.4 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H),7.17 (s, 1H), 6.70 (s, 1H), 4.70 (q, J=14.2, 7.0 Hz, 1H), 4.37-4.21 (m,7H), 4.16-4.10 (m, 2H), 4.09-4.03 (m, 1H), 3.74-3.67 (m, 2H), 3.68-3.59(m, 4H), 3.49-3.45 (m, 1H), 2.99-2.84 (m, 3H), 2.80-2.71 (m, 2H), 2.63(dd, J=16.5, 7.5 Hz, 1H), 2.46-2.25 (m, 4H), 2.07 (t, J=7.9 Hz, 2H),2.05-1.76 (m, 20H, AcOH), 1.74-1.58 (m, 6H), 1.56-1.42 (m, 5H), 1.32 (d,J=8.0 Hz, 2H), 1.18 (d, J=7.0 Hz, 3H), 1.14 (d, J=7.1 Hz, 3H), 0.88-0.74(m, 18H).

Compound 12: Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.29 (d, J=7.5 Hz, 1H), 8.17 (d, J=7.7 Hz, 1H),8.09 (d, J=7.4 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H),7.90 (d, J=8.7 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H),7.58 (d, J=6.4 Hz, 1H), 7.25-7.19 (m, 4H), 7.18-7.12 (m, 2H), 6.71 (s,1H), 4.54-4.44 (m, 2H), 4.37 (q, J=8.3 Hz, 1H), 4.33-4.21 (m, 5H),4.19-4.10 (m, 2H), 4.09-4.02 (m, 1H), 3.64-3.53 (m, 5H), 3.51-3.45 (m,2H), 3.00 (dd, J=9.6 Hz, 1H), 2.89-2.82 (m, 2H), 2.80-2.71 (m, 3H),2.46-2.36 (m, 2H), 2.24 (t, J=7.4 Hz, 2H), 2.08 (t, J=8.0 Hz, 2H),2.00-1.70 (m, 18H, AcOH), 1.69-1.64 (m, 2H), 1.63-1.56 (m, 2H),1.55-1.47 (m, 3H), 1.34 (s, 2H), 1.16 (t, J=6.9 Hz, 6H), 0.87-0.76 (m,12H).

Compound 26: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu Acetate

¹H NMR (600 MHz, DMSO) δ 8.25 (s, 1H), 8.09 (d, J=7.5 Hz, 1H), 7.94 (d,J=7.6 Hz, 1H), 7.89 (d, J=8.3 Hz, 2H), 4.53-4.46 (m, 1H), 4.39 (dd,J=8.3, 4.2 Hz, 1H), 4.34 (dd, J=8.4, 3.8 Hz, 1H), 4.31-4.19 (m, 3H),4.13 (dd, J=15.1, 7.7 Hz, 1H), 3.71-3.49 (m, 5H), 2.94-2.77 (m, 2H),2.33-2.20 (m, 2H), 2.06-1.77 (m, 13H, AcOH), 1.77-1.56 (m, 6H), 1.46 (t,J=7.3 Hz, 2H), 1.25-1.11 (m, 6H), 0.95-0.76 (m, 12H).

Compound 27: Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, D₂O) δ 4.61 (dd, J=9.6, 4.4 Hz, 1H), 4.44-4.22 (m, 8H),4.09-3.99 (m, 2H), 3.85-3.72 (m, 2H), 3.69-3.57 (m, 2H), 2.94 (t, J=7.4Hz, 2H), 2.79-2.63 (m, 2H), 2.43-2.16 (m, 7H), 2.09-1.74 (m, 19H, AcOH),1.73-1.47 (m, 7H), 1.48-1.13 (m, 6H), 1.00-0.79 (m, 21H).

Compound 28: Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ8.28 (d, J=7.8 Hz, 1H), 8.13-7.87 (m, 3H), 7.57(d, J=6.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.15 (s, 1H), 6.69 (s, 1H),4.40-4.31 (m, 2H), 4.29-4.21 (m, 2H), 4.19-4.02 (m, 3H), 3.67-3.60 (m,1H), 3.59-3.53 (m, 2H), 2.92-2.85 (m, 1H), 2.80-2.70 (m, 3H), 2.47-2.38(m, 1H), 2.38-2.31 (m, 1H), 2.08 (t, J=7.9 Hz, 2H), 2.04-1.76 (m, 14H,AcOH), 1.74-1.41 (m, 11H), 1.41-1.14 (m, 2H), 0.91-0.74 (m, 18H).

Compound 30: Ala-Glu-Pro-Val-Pro-Leu Acetate

¹H NMR (600 MHz, DMSO) δ8.29 (d, J=7.1 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 4.54 (d, J=5.4 Hz, 1H), 4.42-4.38 (m, 1H),4.37-4.28 (m, 2H), 4.09 (dd, J=14.2, 8.5 Hz, 1H), 3.66-3.46 (m, 5H),2.28 (t, J=7.4 Hz, 2H), 2.13-1.71 (m, 16H, AcOH), 1.71-1.58 (m, 2H),1.53-1.32 (m, 2H), 1.18 (d, J=6.9 Hz, 3H), 0.90-0.83 (m, 9H), 0.80 (d,J=6.6 Hz, 3H).

Compound 31: Glu-Pro-Val-Pro-Leu Acetate

¹H NMR (600 MHz, DMSO) δ7.94-7.86 (m, 2H), 4.44 (dd, J=8.3, 4.5 Hz, 1H),4.37-4.27 (m, 2H), 4.13 (q, J=7.6 Hz, 1H), 3.74-3.69 (m, 1H), 3.66-3.42(m, 4H), 2.40-2.25 (m, 2H), 2.06-1.58 (m, 17H, AcOH), 1.46 (t, J=7.3 Hz,2H), 0.89-0.84 (m, 9H), 0.81 (d, J=6.5 Hz, 3H).

Compound 32: Pro-Val-Pro-Leu Acetate

¹H NMR (600 MHz, DMSO) δ8.15 (d, J=9.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H),4.35 (dt, J=10.1, 5.2 Hz, 2H), 4.22-4.02 (m, 1H), 3.67-3.59 (m, 2H),3.56 (q, J=13.2, 9.3 Hz, 1H), 2.96-2.88 (m, 1H), 2.86-2.76 (m, 1H),2.05-1.59 (m, 11H, AcOH), 1.59-1.42 (m, 2H), 0.91-0.72 (m, 12H).

Compound 34: Pro-Ala-Ala-Glu-Pro-Val Acetate

¹H NMR (600 MHz, DMSO) δ 8.01 (d, J=7.3 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H),4.49 (q, J=6.8 Hz, 1H), 4.31-4.22 (m, 3H), 3.75 (dd, J=7.8, 4.7 Hz, 1H),3.70-3.61 (m, 2H), 2.88-2.81 (m, 1H), 2.81-2.75 (m, 1H), 2.27-2.13 (m,2H), 2.01-1.64 (m, 18H, AcOH), 1.58 (p, J=6.9 Hz, 2H), 1.17 (dd, J=10.2,7.1 Hz, 6H), 0.78 (dd, J=6.9, 3.5 Hz, 6H).

Compound 35: Pro-Ala-Ala-Glu-Pro Acetate

¹H NMR (600 MHz, DMSO) δ 8.28 (s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.90 (d,J=7.7 Hz, 1H), 4.49 (dd, J=13.7, 7.7 Hz, 1H), 4.35-4.13 (m, 3H),3.76-3.50 (m, 3H), 2.97-2.79 (m, 2H), 2.33-2.18 (m, 2H), 2.16-1.77 (m,10H, AcOH), 1.73-1.58 (m, 4H), 1.26-1.13 (m, 6H).

Compound 45: Ala-Glu-Pro-Val Acetate

¹H NMR (600 MHz, DMSO) δ 8.36 (d, J=7.4 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),4.65-4.53 (m, 1H), 4.35 (dd, J=8.6, 3.4 Hz, 1H), 3.89 (dd, J=7.9, 5.4Hz, 1H), 3.74-3.53 (m, 3H), 2.38-2.19 (m, 2H), 2.05-1.64 (m, 10H, AcOH),1.27-1.17 (m, 3H), 0.83 (d, J=7.1 Hz, 6H).

Compound 48: Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.33 (d, J=7.6 Hz, 1H), 8.27 (d, 1H), 8.21 (t,J=5.8 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 8.05-7.97 (m, 2H), 7.93 (d, J=8.5Hz, 1H), 7.57 (d, J=6.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.16 (s, 1H),6.70 (s, 1H), 4.53-4.47 (m, 1H), 4.38 (dd, J=8.2, 4.2 Hz, 1H), 4.35-4.20(m, 5H), 4.18-4.09 (m, 2H), 4.06 (s, 1H), 3.75-3.50 (m, 8H), 2.93-2.69(m, 5H), 2.45-2.41 (m, 1H), 2.41-2.30 (m, 1H), 2.25 (t, J=7.3 Hz, 2H),2.08 (t, J=7.9 Hz, 2H), 2.01-1.76 (m, 15H, AcOH), 1.74-1.53 (m, 8H),1.53-1.40 (m, 4H), 1.33 (d, J=7.2 Hz, 2H), 1.20 (t, J=9.0 Hz, 3H),0.91-0.73 (m, 18H).

Compound 50: Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Lys-Gln-Asn Acetate

¹H NMR (600 MHz, DMSO) δ 8.49 (d, J=7.8 Hz, 1H), 8.17-8.06 (m, 2H),8.05-7.99 (m, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.59(s, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.37 (d, J=6.9 Hz, 1H), 7.10 (s, 1H),6.68 (d, J=15.7 Hz, 2H), 4.48 (d, J=5.1 Hz, 1H), 4.39 (dd, J=8.1, 4.3Hz, 1H), 4.35-4.19 (m, 6H), 4.17-4.10 (m, 1H), 4.05-3.97 (m, 2H),3.67-3.48 (m, 6H), 2.92-2.78 (m, 2H), 2.78-2.66 (m, 3H), 2.44-2.34 (m,1H), 2.33-2.20 (m, 3H), 2.07 (t, J=7.8 Hz, 2H), 2.01-1.76 (m, 15H,AcOH), 1.75-1.62 (m, 6H), 1.62-1.53 (m, 3H), 1.49-1.29 (m, 6H),1.19-1.12 (m, 6H), 0.91-0.73 (m, 18H).

Compound 51: Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Val-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.51 (d, J=7.6 Hz, 1H), 8.08 (d, J=7.3 Hz, 1H),8.03-7.96 (m, 2H), 7.95-7.89 (m, 2H), 7.78 (d, J=8.9 Hz, 1H), 7.75-7.69(m, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.18 (s, 1H), 6.68 (s, 1H), 4.51 (d,J=5.4 Hz, 1H), 4.40 (dd, J=8.2, 4.2 Hz, 1H), 4.35-4.12 (m, 10H),4.01-3.95 (m, 1H), 3.69-3.51 (m, 4H), 3.09 (d, J=6.4 Hz, 2H), 2.45-2.40(m, 1H), 2.39-2.34 (m, 1H), 2.27 (dd, J=13.4, 6.7 Hz, 2H), 2.21-2.13 (m,1H), 2.06 (t, J=8.0 Hz, 2H), 2.02-1.75 (m, 18H, AcOH), 1.75-1.58 (m,5H), 1.44 (t, J=7.3 Hz, 2H), 1.22 (d, J=7.1 Hz, 3H), 1.16 (d, J=7.0 Hz,3H), 0.88 (d, J=6.7 Hz, 3H), 0.85 (dd, J=6.5, 2.7 Hz, 6H), 0.83-0.77 (m,15H).

Compound 52: Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.28 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.09 (d,J=7.5 Hz, 1H), 7.99-7.92 (m, 2H), 7.87 (dd, J=16.4, 8.8 Hz, 2H), 7.68(d, J=8.5 Hz, 1H), 7.57 (d, J=6.1 Hz, 1H), 7.17 (s, 1H), 6.70 (s, 1H),4.50-4.45 (m, 1H), 4.44-4.35 (m, 2H), 4.32-4.21 (m, 4H), 4.18-4.10 (m,3H), 4.08-3.99 (m, 1H), 3.66-3.49 (m, 6H), 2.90-2.82 (m, 1H), 2.82-2.72(m, 3H), 2.46-2.30 (m, 2H), 2.27-2.23 (m, 1H), 2.07 (t, J=7.9 Hz, 2H),2.01-1.76 (m, 19H, AcOH), 1.75-1.60 (m, 5H), 1.60-1.45 (m, 5H),1.39-1.25 (m, 2H), 1.20-1.10 (m, 6H), 0.88 (d, J=6.6 Hz, 3H), 0.86-0.76(m, 15H).

Compound 56: Pro-Ile-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.27 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H),8.10 (d, J=9.4 Hz, 1H), 8.05-7.97 (m, 2H), 7.92 (q, J=13.5, 8.1 Hz, 2H),7.57 (d, J=6.3 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 6.70 (s,1H), 4.54-4.45 (m, 1H), 4.39 (dd, J=8.3, 4.2 Hz, 1H), 4.35-4.22 (m, 5H),4.21-4.09 (m, 3H), 4.10-4.00 (m, 1H), 3.67-3.48 (m, 6H), 3.41-3.16 (m,4H), 2.95-2.86 (m, 1H), 2.81-2.68 (m, 3H), 2.47-2.41 (m, 1H), 2.41-2.32(m, 1H), 2.25 (t, J=7.6 Hz, 2H), 2.08 (t, J=7.9 Hz, 2H), 2.02-1.75 (m,19H, AcOH), 1.75-1.55 (m, 9H), 1.54-1.36 (m, 5H), 1.33 (d, J=7.0 Hz,2H), 1.15 (d, J=7.1 Hz, 3H), 0.89-0.784 (m, 8H), 0.82-0.76 (m, 14H).

Compound 57: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.31 (d, J=7.8 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H),8.09 (d, J=7.5 Hz, 1H), 8.03 (t, J=7.7 Hz, 2H), 7.96-7.87 (m, 2H), 7.58(d, J=6.3 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 4.49 (q, J=5.3 Hz, 1H), 4.39(dd, J=8.2, 4.4 Hz, 1H), 4.35-4.20 (m, 7H), 4.19-4.12 (m, 2H), 4.10-4.00(m, 1H), 3.67-3.49 (m, 7H), 2.91-2.84 (m, 2H), 2.84-2.70 (m, 4H),2.46-2.38 (m, 1H), 2.38-2.33 (m, 1H), 2.29-2.18 (m, 4H), 2.04-1.76 (m,19H, AcOH), 1.76-1.55 (m, 8H), 1.55-1.41 (m, 5H), 1.32 (s, 2H),1.21-1.11 (m, 6H), 0.94-0.73 (m, 18H).

Compound 58: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asn-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.28 (d, J=7.1 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H),8.09 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.00-7.89 (m, 3H), 7.50(d, J=8.6 Hz, 1H), 7.44 (d, J=6.0 Hz, 1H), 7.30 (s, 1H), 6.80 (s, 1H),4.56-4.46 (m, 2H), 4.38 (dd, J=8.1, 4.3 Hz, 1H), 4.35-4.20 (m, 6H),4.18-4.12 (m, 1H), 4.04-4.00 (m, 1H), 3.66-3.49 (m, 6H), 2.93-2.84 (m,1H), 2.83-2.71 (m, 3H), 2.43-2.31 (m, 3H), 2.25 (t, J=8.0 Hz, 2H),2.04-1.57 (m, 26H, AcOH), 1.56-1.46 (m, 3H), 1.46-1.43 (m, 2H),1.35-1.27 (m, 2H), 1.20-1.10 (m, 6H), 0.86 (dd, J=14.8, 7.9 Hz, 9H),0.81-0.76 (m, 9H).

Compound 60: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu Acetate

¹H NMR (600 MHz, DMSO) δ 8.51 (d, J=8.0 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H),8.10 (d, J=7.4 Hz, 1H), 8.04 (d, J=6.2 Hz, 2H), 7.96 (d, J=7.7 Hz, 1H),7.93 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.6 Hz, 1H),7.11 (s, 1H), 6.71 (s, 1H), 4.48 (d, J=5.4 Hz, 1H), 4.39 (dd, J=8.1, 4.3Hz, 1H), 4.34-4.18 (m, 7H), 4.18-4.10 (m, 1H), 4.07-3.99 (m, 1H), 3.83(q, J=12.8, 6.5 Hz, 2H), 3.69-3.48 (m, 7H), 2.92-2.83 (m, 1H), 2.81-2.62(m, 4H), 2.31-2.02 (m, 7H), 2.01-1.75 (m, 22H, AcOH), 1.74-1.25 (m,16H), 1.20-1.11 (m, 6H), 0.91-0.83 (m, 9H), 0.81-0.76 (m, 9H).

Compound 62: Pro-Ala-Ile-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 8.31-8.23 (m, 1H), 8.20 (d, J=7.5 Hz, 1H), 8.03(d, J=7.7 Hz, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.93-7.85 (m, 2H), 7.57 (d,J=6.6 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.16 (s, 1H), 6.70 (s, 1H), 4.49(d, J=5.5 Hz, 1H), 4.41-4.20 (m, 6H), 4.19-4.00 (m, 5H), 3.71-3.61 (m,2H), 3.61-3.47 (m, 4H), 2.91-2.73 (m, 4H), 2.45-2.39 (m, 1H), 2.39-2.29(m, 1H), 2.24 (t, J=7.1 Hz, 2H), 2.07 (t, J=7.9 Hz, 2H), 2.02-1.76 (m,20H, AcOH), 1.74-1.47 (m, 12H), 1.47-1.29 (m, 5H), 1.16 (d, J=6.9 Hz,3H), 1.04 (d, J=8.4 Hz, 1H), 0.89-0.84 (m, 8H), 0.83-0.72 (m, 16H).

Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Arg-Gln-Asp Acetate

¹H NMR (600 MHz, DMSO) δ 9.30 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.19 (d,J=7.9 Hz, 1H), 8.09 (d, J=7.4 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.98 (d,J=7.0 Hz, 1H), 7.96-7.89 (m, 3H), 7.52 (d, J=8.9 Hz, 1H), 7.11 (s, 1H),6.69 (s, 1H), 4.49 (d, J=5.3 Hz, 1H), 4.39 (dd, J=8.2, 4.3 Hz, 1H), 4.34(d, J=4.3 Hz, 1H), 4.31-4.21 (m, 5H), 4.20-4.10 (m, 3H), 3.68-3.49 (m,6H), 3.13 (d, J=6.1 Hz, 1H), 3.00-2.93 (m, 1H), 2.92-2.85 (m, 1H),2.83-2.76 (m, 1H), 2.41-2.32 (m, 1H), 2.25 (t, J=8.2 Hz, 2H), 2.09-2.03(m, 2H), 2.02-1.76 (m, 20H, AcOH), 1.74-1.70 (m, 1H), 1.69-1.56 (m, 7H),1.55-1.39 (m, 4H), 1.22-1.11 (m, 6H), 0.93-0.83 (m, 9H), 0.83-0.77 (m,9H).

Compound 73: Val-Pro-Leu-Val Acetate

¹H NMR (600 MHz, MeOD) δ 4.54-4.49 (m, 1H), 4.40 (dd, J=9.2, 6.0 Hz,1H), 4.18 (d, J=5.0 Hz, 1H), 3.99 (d, J=5.3 Hz, 1H), 3.69 (dd, J=10.7,5.0 Hz, 1H), 3.65-3.58 (m, 1H), 2.32-2.20 (m, 2H), 2.19-2.01 (m, 3H),2.00-1.86 (m, 4H, AcOH), 1.85-1.75 (m, 1H), 1.69-1.54 (m, 2H), 1.12 (d,J=7.0 Hz, 3H), 1.03-1.01 (m, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.93-0.89 (m,9H).

Example 2: Anti-Ulcer Effect of Polypeptide (Compound 1) onEthanol-Induced Gastric Ulcer in Mice

1. Experimental Animal:

SPF grade C57BL/6 mice, from Chengdu Yaokang Biotechnology Ltd, animallicense number: SCXK (Chuan) 2020-034.

2. Method:

After adaptive feeding, the mice were randomly divided into four groupswith 10 mice in each group, namely, control group (normal group), modelgroup (modeling with absolute ethanol), positive drug group (teprenone160 mg/kg) and compound 1 group (1 mg/kg). After the animals weregrouped, the control group and model group were treated with pure water,and the other dosed groups were treated with the corresponding drugsonce a day for 8 consecutive days. On the 7th day, after treatment, allthe animals were fasted for 24 h with free access to water. On the 8thday, 30 min after administration, the mice in each group (except thecontrol group) were given 0.15 mL of absolute ethanol by oral gavage;and after 1 h, the animals were sacrificed by excessive CO₂ inhalation,the gastric cardia was ligated, the pylorus was occluded, and the wholestomach was removed. 1 mL of 1% formaldehyde solution was injected intothe gastric lumen, the cardia was ligated, and the stomach was taken outand immediately immersed in 1% formaldehyde solution for fixation of 25min. The stomach was cut open along the greater curvature, the contentof the stomach was cleaned off with normal saline, and the ulcer indexwas calculated after being laid flat. Calculation method for ulcerindex: If the length of cord-like injury was greater than 1 mm, thelength thereof was measured, with 1 point per millimeter; if the widththereof was greater than 1 mm, the score thereof was doubled accordingto the number of millimeters of the width; and if the length was lessthan 1 mm, a score of 0.5 was given, and the scores were added up toobtain the ulcer index of the animal.

3. Results:

In the mouse ethanol-induced gastric ulcer model, oral gavage ofCompound 1 once a day for 8 consecutive days could significantly reducethe gastric ulcer index of mice, and the effect was greater than that ofthe positive drug group (Table 6). The results showed that Compound 1had a significant effect on treating gastric ulcer. The experimentalresults were shown in FIG. 2 .

TABLE 6 Effects of test drugs on the ulcer index of mice withethanol-induced gastric ulcer (n = 10, x ± s) Group Ulcer index Controlgroup 1.84 ± 1.62 Model group  35.32 ± 23.30^(##) Teprenone group: 13.42± 7.61* Compound 1 group  8.13 ± 4.17** Note:, ^(##)P < 0.01, comparedwith the control group; and *P < 0.05, **P < 0.01, compared with themodel group.

Example 3: Anti-Ulcer Effect of Some Polypeptide Samples Obtained fromExample 1 on Ethanol-Induced Gastric Ulcer Model in Mice

1. Experimental Animal:

SPF grade C57BL/6 mice, from Chengdu Yaokang Shengwu Keji YouxianGongsi, animal license number: SCXK (Chuan) 2020-034.

2. Method:

After adaptive feeding, all the animals were fasted for 24 h with freeaccess to water after administration one day before the experiment.Before modeling, the experimental mice were randomly divided intogroups: blank group (5 mice), model group (10 mice), and treatmentgroups (10 mice per group). Except for the blank group and the modelgroup, which were given sterile water by gavage, the treatment groupswere administered with different test compounds by gavage at a dose of0.2 mg/kg, respectively. One hour after administration, the micereceived 0.9 ml/kg absolute ethanol by oral gavage for modeling. After 1h, the animals were sacrificed by cervical dislocation, the gastriccardia was ligated, the pylorus was occluded, and the whole stomach wasremoved. 1 mL of 1% formaldehyde solution was injected into the gastriclumen, the cardia was ligated, and the stomach was taken out andimmediately immersed in 1% formaldehyde solution. After 30 min, thestomach tissue was taken out and cut open along the greater curvature.The content of the stomach was rinsed off with normal saline, the injuryof gastric mucosa in mice were observed and measured after being laidflat, and the ulcer index and ulcer inhibition rate were calculated.

Calculation method for ulcer index: If the length of cord-like injurywas greater than 1 mm, the length thereof was measured, with 1 point permillimeter; if the width thereof was greater than 1 mm, the scorethereof was doubled according to the number of millimeters of the width;and if the length was less than 1 mm, a score of 0.5 was given, and thescores were added to obtain the ulcer index of the animal.

Ulcer inhibition rate=(ulcer index of model group−ulcer index oftreatment group)/ulcer index of model group*100%; and

Relative ulcer inhibition rate=(ulcer inhibition rate of testcompound)/(ulcer inhibition rate of Compound 1).

3. Results:

Table 7 showed the relative ulcer inhibition rates of the compounds ofthe present invention

TABLE 7 Anti-ulcer activity of single administration in ethanol-inducedmodel in mice Anti-ulcer No. activity * 1 +++ 2 ND 3 +++ 4 ND 5 ND 6 ND7 ND 8 + 9 ND 10 ++++ 11 ++ 12 / 13 ND 14 ND 15 ND 16 ND 17 ND 18 ND 19ND 20 ND 21 ND 22 ND 23 ND 24 ND 25 ND 26 +++ 27 +++ 28 +++ 29 ND 30 +++31 +++ 32 +++ 33 ND 34 / 35 + 36 ND 37 ND 38 +++ 39 ND 40 ND 41 ND 42 ND43 ND 44 + 45 − 46 ND 47 ND 48 ++ 49 ND 50 / 51 ND 52 ND 53 ND 54 ND 55ND 56 − 57 ++ 58 / 59 ND 60 ND 61 ND 62 ND 63 ND 64 + 65 ND 60 + 67 + 68ND 69 ND 70 ND 71 ND 72 ND 73 ++ * Note: The anti-ulcer effect of eachcompound was completed by several cohorts of experiments. For easycomparison, the anti-ulcer activity was expressed as the mean value ofthe relative ulcer inhibition rate (Compound 1 was used as a controlgroup in each cohort of experiments). Relative ulcer inhibition rate =(ulcer inhibition rate of test compound)/(ulcer inhibition rate ofCompound 1) Relative ulcer inhibition rate >1.20, denoted as “++++”;relative ulcer inhibition rate 0.9-1.20, denoted as “+++”; relativeulcer inhibition rate 0.6-0.9, denoted as “++”; relative ulcerinhibition rate 0.3-0.6, denoted as “+”; 0< relative ulcer inhibitionrate <0.3, denoted as “/” (very low activity); relative ulcer inhibitionrate <0, denoted as “−”; and ND represented no comparison with Compound1.

Example 4: Effect of Compound 1 on Mouse Gastric Organoid

Method:

The gastric antrum epithelium of healthy wild-type mice was used fororganoid culture. The epithelial layer of the gastric antrum of the micewas separated from the muscle layer under stereoscope, cut into smallpieces about 0.5 mm in size, and digested with 2.5 mM EDTA/DPBS at 4° C.for about 1 h. The digested gastric glandular epithelial cells werefiltered and centrifuged, and the supernatant was discarded. Theobtained cell pellet was resuspended in matrix gel and seeded in aculture dish followed by addition of organoid medium containing growthfactors. In the control group, no test drug was added except growthfactors. In the experimental group, Compound 1 was added under the sameculture conditions as in the control group. The ball formation andorganoid growth were observed and photographed at Day 1, Day 3, Day 5and Day 7 with an inverted microscope, and the effect of Compound 1 onorganoid growth was assessed.

Results:

Compared with the control group, the growth rate of the organoids in theculture medium containing Compound 1 was obviously accelerated overtime. Through the quantitative analysis of the diameter of eachorganoids, the results showed that the volume of the organoids treatedwith Compound 1 was significantly larger than that of the control group(see FIG. 3 , *p<0.05, compared with the control group), and theproliferation of the organoids could be significantly promoted (all thestatistical data also showed significant difference). RNA was extractedfrom the organoids, and the transcription level of target genes wasdetected by real-time fluorescence quantitative PCR. It was discoveredthat the mRNA levels of the endocrine cell markers SST and

Gastrin and the neck mucus cell marker TFF2 increased significantly (seeFIG. 4 ). These results indicated that the polypeptide Compound 1 couldpromote the proliferation and differentiation of gastric organoid,indicating that Compound 1 participated in and regulated theproliferation and differentiation of gastric epithelial stem cells.

Example 5: Therapeutic Effect of Compound 1 on Chronic AtrophicGastritis Model in Mice

Method:

Chronic atrophic gastritis (Lgr5-GFP-CreERT mice) was induced by MNNG(N-methyl-N-nitro-N-nitrosoguanidine) combined with ranitidine. The micewere free to access to an aqueous solution containing MNNG (100 mg/ml),and at the same time, the mice were given ranitidine (8 mg/ml) aqueoussolution at a dose of 150 mg/kg by gavage at a fixed time per day for 20consecutive weeks. After 20 weeks of modeling, on the basis of drinkingordinary distilled water, the mice were given Compound 1 (5 mg/kg) dailyby gavage. After 2 weeks of administration, the therapeutic effect ofCompound 1 on chronic atrophic gastritis was observed.

Results:

The results of tissue staining showed that the gland structure in thecorpus and antrum of model group was disordered, accompanied by areduced number of parietal cells (H⁺-K⁺-ATPase positive) and decreasedheight of the mucosal epithelium in the gastric antrum. After 2 weeks oftreatment with Compound 1, compared with the model group, the structureof the gastric was recovered to normal, the number of parietal cellsincreased significantly, and the height of the mucosa in the gastricantrum was substantially recovered to the normal state. The results wereshown in FIG. 5 . These results indicated that Compound 1 could promotethe repair of chronic atrophic gastritis in mice.

In chronic atrophic gastritis, the epithelial repair process entailsstem cells. We detected the change in the gastric epithelial stem cells(Lgr5⁺ and AQP5⁺) by immunofluorescence staining. The experimentalresults showed that compared with the control group, the number of stemcells in the model group decreased significantly; and compared with themodel group, the number of proliferatively active stem cells(PCNA-positive Lgr5⁺ cells and Ki67-positive AQP5⁺ cells) in theCompound 1 treatment group also increased significantly, and all thestatistical results had significant difference. The results were shownin FIG. 6 .

Example 6: Therapeutic Effect of Compound 1 on Rats with ChronicAtrophic Gastritis

1. Experimental Animals

85 SPF grade SD rats, half male and half female, weighing 160-280 g,were provided by SPF (Beijing) Biotechnology Co., Ltd. with the licensenumber: SOCK (Jing) 2016-0002.

2. Experimental Method

85 SD rats were fed adaptively for one week and then randomly dividedinto a blank control group (10 rats) and a chronic atrophic gastritismodel group (abbreviated as CAG group) (75 rats). The blank controlgroup was given 5 ml/kg deionized water daily by gavage, with normaldiet and free access to water. The CAG group was given 120 μg/mL MNNG(N-methyl-N-nitro-N-nitrosoguanidine) aqueous solution daily by gavage,at 5 ml/kg, with free access to 0.03% ranitidine feed, 2% sodiumsalicylate and water. After fasting for 18 hours every week from the15th week, a hot starch paste (5 ml/kg, 60-70° C.), instead of MNNG, wasgiven by gavage. The rest treatment was the same as hereinbefore. Fromthe 18th week, two male and two female rats in the model group wererandomly selected every two weeks, the gastric mucosa was taken forpathological evaluation until the model was successful (reduction ofintrinsic glands+intestinal metaplasia), and 19 rats died during themodeling process. At the 25th week of modeling, the CAG rats wererandomly divided into three groups: a model group, a Compound 1high-dose group (3 mg/kg) and a low-dose Compound 1 group (1 mg/kg). Thenormal control and model groups were given the same volume of normalsaline by gavage daily, and each of the other groups was given thecorresponding drug by gavage for 8 weeks.

During the experiment, the weight changes of the rats were recorded, thefood intake and water consumption were measured every week, the activitystatus of the rats was observed, etc., at regular intervals every week.After 8 weeks of administration, the rats were fasted for 24 hours withfree access to water and were anesthetized by intraperitoneal injectionof 10% chloral hydrate at 3.5 ml/kg. The whole stomach was removed, thenquickly cut open along the greater curvature, and rinsed with normalsaline, and gastric mucosa tissues were taken from the whole lessercurvature and the near greater curvature up from the esophagus end downto the duodenum end, fixed in 10% neutral formalin solution,conventionally embedded with paraffin, sectioned and conventionallystained with HE, and the pathological results were analyzed.

All data were processed by SPSS23 software. The measurement data wassubjected to normality test by Shapiro-Wilk test. If it conformed tonormal distribution, it was expressed by the mean±standard deviation(X±S). The mean values were compared between multiple groups by One-wayANOVA. Those with equal variances were compared between groups by LSDmethod, while those without equal variances were compared between groupsby Dunnett's T3 method. P<0.05 indicated that the difference wasstatistically significant. If it did not conform to normal distribution,rank sum test was performed, Kruskal-Wallis test was used for comparisonbetween multiple groups, and Mann-Whitney test was used for pairwisecomparison between groups. The grade data was the same as in the testmethod of non-normal distribution. P<0.05 indicated that the differencewas statistically significant.

3. Results

3.1 General Condition of Rats

The rats in the normal group had smooth and dense body hair and whiteand shiny hair color. The degree of activity was relatively high, andthe responsiveness to activities such as rearing cage movement andfeeding with food and water, and sounds was high. The mental state wasgood, and the mood was stable during gavage, weighing and otheroperations. The body hair of the rats in the model group was withered,sparse and easy to fall off and had a dull and beige color. The rats hadlow mobility, liked to curl up and had low responsiveness to activitiessuch as rearing cage movement and feeding with food and water, and themental state thereof was sluggish. The rats were prone to mood swingsand the behavior of biting and scratching the experiment operatorsduring gavage, weighing and other operations. The low- and high-doseCompound 1 groups both improved the whole condition of the rats, e.g.,in terms of mobility and responsiveness, to various extents.

3.2 Weight of Rats

After 8 weeks of administration, there was no significant difference inthe weights of the female rats in each group. Compared with the normalgroup, the weights of the male rats in the model group significantlydecreased (P<0.05); compared with the model group, the weights of themale rats in the low- and high-dose Compound 1 groups significantlyincreased (P<0.05), and in each of the other groups, the difference inweight was not statistically significant, as shown in Table 8.

TABLE 8 Weight (g) in each group after 8 weeks of administration No. ofWeight of female Weight of male Group animals rat (mean) rat (mean)Blank control group 10 364 602  Model group 12 369 446^(#) Compound 1,high 14 396 637* Compound 1, low 14 374 532* Note: ^(#)P < 0.05,compared with the normal group; and *P < 0.05, compared with the modelgroup.

3.3 Pathological Results

Microscopic observation of pathological sections of gastric mucosa inrats: The rats in the normal group had a clear structure of each layerin the mucosa, compact and orderly arrangement of glands, and no chronicinflammation in the mucosal layer; and the rats in the model group hadinflammatory cell infiltration in gastric mucosa, mucosal musclehyperplasia, various degrees of reduction of glands in lamina propria,sparse and irregular arrangement, dilation of some glands, no intestinalmetaplasia, and dysplasia in few cases. The scores of inflammation andatrophy in the model group were significantly increased (P<0.05); andcompared with the model group, the low- and high-dose Compound 1 groupscould significantly improve the degree of inflammation and atrophy ofgastric mucosa in rats (P<0.05). The results were shown in FIG. 7 .

Example 7: Effect of Compound 1 on the Proliferation of HaCAT Cells

Method:

HaCAT cells were adjusted to a concentration of 1.0*10⁵ to 5.0*10⁵/mLfor passaging and cultured at 37° C. and 5% CO₂ for 24-36 hours forbiological activity detection. The cells were digested by trypsin,collected, prepared into a concentration of 2.5*10⁴/mL with a serum-freemedium, seeded in a 96-well cell culture plate with 100 μL per well,i.e., 2500 cells/well, and cultured overnight at 37° C. and 5% CO₂. 50μL of a compound solution formulated with the serum-free medium wasfurther added to make the final concentration of Compound 1 0.4 ug/mL.An EGF control group was performed in parallel by adding 50 μL of arecombinant human epidermal growth factor (EGF) with a finalconcentration at 100 ng/mL. In the model control group, an equal volumeof serum-free medium was added. After culturing at 37° C. and 5% CO₂ for72 hours, the proliferation of the HaCAT cell line was detected by theCellTiter-Glo® kit.

Results:

As shown in FIG. 8 , 0.4 μg/mL Compound 1 had a significantproliferation-promoting effect on HaCAT cells, indicating that Compound1 had a good effect on epidermal growth and skin injury repair. In FIG.8 , compared with the model control group, * represented p<0.05, and **represented p<0.01.

Example 8: Repair Effect of Compounds 1 and 26 on Vascular Injury inZebrafish

Method:

The blood vessels of transgenic vascular green fluorescent zebrafish(Fli-1) were labeled by green fluorescent protein, which was clearlyvisible under a fluorescence microscope (FIG. 9 , the dotted frame inFIG. 9 (yellow in the original picture) was the intestinal blood vesselat the analysis site, and the arrow (white in the original picture)pointed to subintestinal vascular branches), and it became a modelorganism for observing vascular change. Zebrafish Fli-1 was naturallymated in pairs for breeding. Zebrafish Fli-1 was randomly selected andplaced in a 6-well plate one day after fertilization, with 30 fish perwell (experimental group). The zebrafish in the normal control groupwere treated with standard dilution water, and each of the otherexperimental groups was induced with aqueous simvastatin for 3 hours toestablish a zebrafish microvascular loss model. After 3 hours, theaqueous solutions in all the groups were replaced with standard dilutionwater, and simvastatin induction was terminated. The test drug groupswere respectively given Compound 1 (500 ng/fish) or Compound 26 (500ng/fish) by intravenous injection and treated at 28° C. for 2 days. Tenzebrafish in each group were randomly selected and photographed underthe fluorescence microscope. NIS-Elements D 3.20 advanced imageprocessing software was used for analysis and data collection, and thenumber of subintestinal vascular branches was analyzed.

Results:

In the model group, it could be seen that the number of subintestinalvascular branches decreased. Intravenous injection of Compounds 1 and 26could significantly reverse subintestinal microvascular loss caused bysimvastatin and restore the number of subintestinal vascular branches ofzebrafish. Compounds 1 and 26 were shown to promote the repair ofinjured blood vessels (FIGS. 10 and 11 ). In FIG. 11 , compared with themodel control group, **p<0.01 and ***p<0.001.

Example 9: Gastric and Intestinal Stability Test of Some PolypeptideSamples

Method:

1 mg of each of the samples to be tested (Compounds 1, 26, 27 and 28 andEGF) were taken and dissolved in 1 ml of water. 100 ul of samplesolution was taken, 900 ul of water was added, and they were uniformlymixed, as a control solution. 100 ul of each sample solution was taken,and 900 ul of artificial gastric juice (W), artificial intestinal juice(X), povidone-iodine solution (I), and hydrogen peroxide solution (O)were respectively added. The solution was placed in a constanttemperature water bath at 37° C. for 1 hour, and left to stand forcooling and filtering, as a test solution. The peak areas of the samplebefore and after treatment were respectively detected by highperformance liquid chromatography, and the experimental results werecompared based on the peak areas of the samples. The original solutionwithout any treatment after being diluted with water was used as acontrol, and the changes in the peak areas (contents) of test solutionsat corresponding positions were compared and counted.

TABLE 9 Gastric and intestinal stability test of polypeptide samples W XI O No. Retained % Retained % Retained % Retained % Compound 1 96 0 101100 Compound 26 100 103 101 102 Compound 27 97 0 100 101 Compound 28 960 99 99 EGF 0 0 0 0 Note: W represented artificial gastric juice, Xrepresented artificial intestinal juice, I represented povidone-iodinesolution, and O represented hydrogen peroxide solution.

Results:

As shown in Table 9, the four test products (Compounds 1, 26, 27, and28) all retained 100% in the artificial gastric juice (W),povidone-iodine solution (I) and hydrogen peroxide solution (O),indicating that they were very stable; Compound 26 was also extremelystable in artificial intestinal juice (X); EGF was not retained in boththe gastric juice and intestinal juice, indicating that it was unstablein the gastric juice and intestinal juice, and where EGF was appliedexternally after disinfection with povidone-iodine solution and hydrogenperoxide solution, EGF was also destroyed.

Example 10: Effect of Compound 1 on Aspirin-Induced Gastric Ulcer inRats

Method:

After adaptive feeding, SD rats were divided into three groups (10 ratsin each group) by Excel-based complete randomization, namely, a controlgroup, a model group, and a Compound 1 (0.3 mg/kg) group. After theanimals were grouped, they were given corresponding treatments (thecontrol group and the model group were given the same volume of purifiedwater, and the Compound 1 group was given corresponding drug treatment)once a day for 8 consecutive days. On the 7th day after administration,all the animals were fasted for 24 h with free access to water. On the8th day, except for the control group, the rats in the Compound 1 groupand the model group were orally given 250 mg/kg aspirin solution formodeling 30 min after compound administration (or given water). 4 hafter modeling, the animals were sacrificed, the cardia was ligated, thepylorus was occluded, and the whole stomach was removed. 8 mL of 1%formaldehyde solution was injected into the gastric lumen, the pyloruswas ligated, and the stomach was taken out and immediately immersed in1% formaldehyde solution for fixation. After 30 min, the stomach was cutopen along the greater curvature, the content of the stomach was cleanedoff with normal saline, and after the stomach was laid flat, the stomachwas observed, and panoramic photos were taken to measure the ulcer area.

Results:

Oral gavage of Compound 1 (0.3 mg/kg) once a day for 8 consecutive dayshad no obvious effects on the weight change of the aspirin-inducedgastric ulcer model rats. Compound 1 reduced bleeding points in thestomach of the aspirin-induced gastric ulcer model rats andsignificantly reduced the area of gastric ulcer in the rats. Table 10showed the effect of Compound 1 on aspirin-induced gastric ulcers inrats.

TABLE 10 Effect of Compound 1 on aspirin-induced gastric ulcer in rats.Group/dose Ulcer area (mm²) Control group: 7.42 ± 7.32  Model group:140.36 ± 82.40^(##) Compound 1 group:  20.55 ± 10.45** Note: ^(##)p <0.01, compared with the control group; and **p < 0.01, compared with themodel group,

Although the above examples are disclosed in the present invention, theembodiments of the present invention are not limited to the aboveexamples, and any other changes, modifications, substitutions,combinations, and simplifications that do not depart from the presentinvention should be equivalent replacements and are included in thescope of protection of the present invention.

1. A compound of Formula (I) or a physiologically compatible saltthereof, wherein the compound of Formula (I) is as follows:H-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Val-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁-OH  (I)wherein Xaa₁ is Pro, Gly, Ala or absent; Xaa₂ is Ala, Leu, Ile, Gly,Cys, Ser or absent; Xaa₃ is Ala, Pro, Gly, Leu, Ile, Cys, Ser or absent;Xaa₄ is Glu, Gln, Asp, Asn, Leu, Ile, Val or absent; Xaa₅ is Pro, Gly,Ala, Val or absent; Xaa₆ is Pro, Gly or Ala; Xaa₇ is Leu, Phe, Val, Ala,Tyr, Glu, Lys, Asp, Ile, Met or absent; Xaa₈ is Val, Leu, Gln, Ile, Metor absent; Xaa₉ is Lys, Arg, His, Asp, Val or absent; Xaa₁₀ is Glu, Gln,Asp, Asn or absent; and Xaa₁₁ is Glu, Asp, Asn, Gln or absent, providedthat at most 9 of Xaa₁, Xaa₂, Xaa₃, Xaa₄, Xaa₅, Xaa₇, Xaa₈, Xaa₉, Xaa₁₀and Xaa₁₁ are absent.
 2. The compound or physiologically compatible saltthereof according to claim 1, wherein X_(aa5) is Pro.
 3. The compound orphysiologically compatible salt thereof according to claim 1, whereinX_(aa6) is Pro.
 4. The compound or physiologically compatible saltthereof according to claim 1, wherein X_(aa7) is Leu.
 5. The compound orphysiologically compatible salt thereof according to claim 1, whereinthe compound of formula (I) has a structure of the following Formula(II),H-Xaa₁-Xaa₂-Xaa₃-Xaa₄-Pro-Val-Pro-Leu-Xaa₈-Xaa₉-Xaa₁₀-Xaa₁₁-OH  (II),wherein Xaa₁ is Pro, Gly, Ala or absent; Xaa₂ is Ala, Leu, Ile, Gly,Cys, Ser or absent; Xaa₃ is Ala, Pro, Gly, Leu, Ile, Cys, Ser or absent;Xaa₄ is Glu, Gln, Asp, Asn, Leu, Ile, Val or absent; Xaa₈ is Val, Leu,Gln, Ile, Met or absent; Xaa₉ is Lys, Arg, His, Asp, Val or absent;Xaa₁₀ is Glu, Gln, Asp, Asn or absent; and Xaa₁₁ is Glu, Asp, Asn, Glnor absent.
 6. The compound or physiologically compatible salt thereofaccording to claim 5, wherein Xaa₁ is Pro or absent.
 7. The compound orphysiologically compatible salt thereof according to claim 5, whereinXaa₂ is Ala or absent.
 8. The compound or physiologically compatiblesalt thereof according to claim 5, wherein Xaa₃ is Ala, Gly or absent.9. The compound or physiologically compatible salt thereof according toclaim 5, wherein Xaa₄ is Glu, Gln, Asp or absent.
 10. The compound orphysiologically compatible salt thereof according to claim 5, whereinXaa₈ is Val or absent.
 11. The compound or physiologically compatiblesalt thereof according to claim 5, wherein Xaa₉ is Lys, Arg or absent.12. The compound or physiologically compatible salt thereof according toclaim 5, wherein Xaa₁₀ is Glu, Gln or absent.
 13. The compound orphysiologically compatible salt thereof according to claim 5, whereinXaa₁₁ is Asp or absent.
 14. The compound or physiologically compatiblesalt thereof according to claim 5, wherein one of Xaa₁, Xaa₂, Xaa₃ andXaa₄ is absent; or two of Xaa₁, Xaa₂, Xaa₃ and Xaa₄ are absent; or threeof Xaa₁, Xaa₂, Xaa₃ and Xaa₄ are absent; or all of Xaa₁, Xaa₂, Xaa₃ andXaa₄ are absent.
 15. The compound or physiologically compatible saltthereof according to claim 5, wherein one of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁is absent; or two of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ in Formula (I) or (II)are absent; or three of Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ are absent; or allof Xaa₈, Xaa₉, Xaa₁₀ and Xaa₁₁ are absent.
 16. The compound orphysiologically compatible salt thereof according to claim 1, whereinthe compound is selected from the group consisting of:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 1);Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 2);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys (Compound 3);Pro-Ala-Ala-Glu-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 4);Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys-Gln-Asp (Compound 5);Pro-Ala-Ala-Glu-Pro-Val-Gly-Ala-Val-Lys-Gln-Asp (Compound 6);Pro-Ala-Ala-Glu-Pro-Val-Gly-Val-Val-Lys-Gln-Asp (Compound 7);Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu-Val-Lys-Gln-Asp (Compound 8);Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu (Compound 9);Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 10);Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 11);Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys-Gln-Asp (Compound 12);Pro-Ala-Ala-Glu-Pro-Val-Pro-Tyr-Val-Lys-Gln-Asp (Compound 13);Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys (Compound 14);Pro-Ala-Ala-Glu-Pro-Val-Gly-Val-Val-Lys (Compound 15);Pro-Ala-Ala-Glu-Pro-Val-Ala-Leu-Val-Lys (Compound 16);Pro-Ala-Ala-Glu-Pro-Val-Ala-Val-Val-Lys (Compound 17);Pro-Ala-Ala-Glu-Ala-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 18);Pro-Ala-Ala-Glu-Pro-Val-Ala-Leu-Val-Lys-Gln-Asp (Compound 19);Pro-Ala-Ala-Glu-Ala-Val-Ala-Leu-Val-Lys-Gln-Asp (Compound 20);Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 21);Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys (Compound 22);Pro-Ala-Ala-Glu-Pro-Val-Pro-Tyr-Val-Lys (Compound 23);Pro-Ala-Ala-Glu-Pro-Val-Gly-Phe-Val-Lys (Compound 24);Pro-Ala-Ala-Glu-Pro-Val-Ala-Phe-Val-Lys (Compound 25);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu (Compound 26);Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 27);Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 28);Pro-Ala-Ala-Glu-Pro-Val-Pro (Compound 29); Ala-Glu-Pro-Val-Pro-Leu(Compound 30); Glu-Pro-Val-Pro-Leu (Compound 31); Pro-Val-Pro-Leu(Compound 32); Ala-Ala-Glu-Pro-Val-Pro-Leu (Compound 33);Pro-Ala-Ala-Glu-Pro-Val (Compound 34); Pro-Ala-Ala-Glu-Pro (Compound35); Pro-Ala-Ala-Glu (Compound 36);Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 37);Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 38);Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 39); Pro-Leu-Val-Lys-Gln-Asp(Compound 40); Pro-Ala-Ala-Glu-Pro-Val-Pro-Ile-Val-Lys (Compound 41);Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys (Compound 42);Pro-Ala-Ala-Glu-Pro-Val-Pro-Met-Val-Lys (Compound 43);Ala-Glu-Pro-Val-Pro (Compound 44); Ala-Glu-Pro-Val (Compound 45);Pro-Ala-Ala-Asn-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 46);Pro-Ala-Ala-Leu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 47);Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 48);Pro-Ala-Pro-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 49);Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Lys-Gln-Asn (Compound 50);Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Val-Gln-Asp (Compound 51);Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys-Gln-Asp (Compound 52);Pro-Ala-Ala-Glu-Pro-Val-Pro-Ile-Val-Lys-Gln-Asp (Compound 53);Pro-Ala-Ala-Glu-Pro-Val-Pro-Met-Val-Lys-Gln-Asp (Compound 54);Pro-Leu-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 55);Pro-Ile-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 56);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp (Compound 57);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asn-Asp (Compound 58);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asp-Asp (Compound 59);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (Compound 60);Pro-Ala-Leu-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 61);Pro-Ala-Ile-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 62);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Leu-Lys-Gln-Asp (Compound 63);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ile-Lys-Gln-Asp (Compound 64);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Met-Lys-Gln-Asp (Compound 65);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Arg-Gln-Asp (Compound 66);Pro-Ala-Ala-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 67);Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 68);Gly-Ala-Ala-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 69);Gly-Ala-Gly-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 70);Gly-Ala-Gly-Val-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 71);Pro-Ala-Ala-Glu-Pro-Val-Ala-Phe-Val-Lys-Gln-Asp (Compound 72); andVal-Pro-Leu-Val (Compound 73).
 17. The compound or physiologicallycompatible salt thereof according to claim 5, wherein the compound isselected from the group consisting of:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 1);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys (Compound 3);Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 10);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu (Compound 26);Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 27);Ala-Glu-Pro-Val-Pro-Leu (Compound 30); Glu-Pro-Val-Pro-Leu (Compound31); Pro-Val-Pro-Leu (Compound 32); Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(Compound 28); Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound11); Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 48);Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp (Compound 57); andGlu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Compound 38). 18-23. (canceled) 24.A pharmaceutical composition, a food composition, a health care orcosmetic composition or commodity composition, said compositioncomprising the compound or a physiologically compatible salt thereofaccording to claim 1 and a physiologically acceptable carrier.
 25. Amethod of repairing skin wounds or mucosal damage, comprisingadministering to the subject in need thereof the compound orphysiologically compatible salt thereof according to claim
 1. 26. Amethod for regulating the proliferation and differentiation of stemcells, comprising administering to the subject in need thereof thecompound or physiologically compatible salt thereof according toclaim
 1. 27. The method according to claim 25, wherein the mucosaldamage is mucosal damage in a cavity such as the digestive system orrespiratory system.
 28. The method according to claim 25, wherein themucosal damage of the digestive system is related to oral, esophageal,and gastrointestinal diseases, and the oral diseases include oral ulcer,stomatitis, gingivitis, periodontitis, etc.; the esophageal diseasesinclude esophagitis, esophageal ulcer, etc.; the gastrointestinaldiseases include chronic gastritis, chronic atrophic gastritis, acutegastritis, gastroduodenal ulcer, functional gastrointestinal diseases,dyspepsia, precancerous lesions, digestive system tumors,gastrointestinal bleeding, gastroesophageal reflux disease, acute andchronic enteritis, ulcerative colitis, Crohn's disease, and mucosalinjuries caused by radiotherapy and/or chemotherapy; and the skin woundsis related to diseases such as epidermal inflammation, mechanical andsurgical wound, burns and scalds, ulcers, fistulas, bedsores, and skininjuries caused by radiotherapy and/or chemotherapy.
 29. The methodaccording to claim 28, wherein the mucosal damage of the digestivesystem is mucosal damage caused by an irritant substance or a drug or bya stress state.
 30. A method for preventing, alleviating or treating agastrointestinal disease or eliminating inflammatory edema, comprisingadministering to the subject in need thereof the compound orphysiologically compatible salt thereof according to claim 1.